Approval Processes
The regulatory approval pathway for a new “biological product” submitted as a Biologics License Application (BLA) under the Biologics Price Competition and Innovation Act (BPCIA), is now separate from the approval process for a new “drug” product submitted as a New Drug Application (NDA) under the Hatch-Waxman Act.1 Two separate searchable online databases now exist for approved “drug” and “biological” products, respectively; the Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), and the Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations (Purple Book).2
The Orange Book contains details for “listed drugs,” including certain patents covering the reference listed drug, patent expiration dates, use codes and regulatory exclusivities.3 The Orange Book Transparency Act of 2020, signed into law on January 5, 2021, clarifies, among other things, some of the patent listing requirements, amending the language to require submission of patent information claiming a drug substance (active ingredient), drug product (formulation or composition), or method of use included in the NDA (i.e., a method of use that corresponds with an approved indication/use code).4 The Purple Book contains information on FDA-licensed (approved) “biological products,” including licensed biosimilars, interchangeable products, and reference biological products.5 The Biological Product Patent Transparency Act, signed into law on December 27, 2020, requires any biologic product sponsor providing an applicant for an abbreviated Biologics License Applications (aBLA) for a biosimilar product with a patent list pursuant to the so-called “patent dance” to disclose the patent list along with the patent expiration dates to the FDA within 30 days.6 The FDA is then required to list the patent information in the Purple Book and maintain updated patent listings.7 Unlike the Orange Book, the types of patents that can be subject to the “patent dance” and listed in the Purple Book are not limited to defined categories. For example, method of manufacture patents can be identified in the “patent dance” and listed in the Purple Book.
Transition From Orange Book To Purple Book
The Purple Book originated as two lists: one for drugs approved by the Center for Drug Evaluation and Research (CDER) and one for biologic products approved by the Center for Biologics Evaluation and Research (CBER).8 On February 24, 2020, the FDA released the searchable online Purple Book database replacing both lists.9 Prior to that date, some biologic products were approved through the NDA process, and information related to those approved products was listed in the Orange Book.10 On March 23, 2020, the FDA removed products it “deemed” biological products approved through the NDA process from the Orange Book database and transitioned those products to the Purple Book database.11
What Is A “Biological Product”?
Prior to the BPCIA, “biological product” was defined as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”12 The BPCIA expanded the definition of “biological products” to include any “protein (except any chemically synthesized polypeptide).”13 The terms “protein” and “chemically synthesized polypeptide” were, however, not defined.14 Through draft guidance and comments from the industry, the FDA eventually interpreted the terms as follows: “protein means any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size;” “‘chemically synthesized polypeptide’ means any alpha amino acid polymer that (1) is made entirely by chemical synthesis; and (2) is less than 100 amino acids in size.”15 The FDA’s interpretation of “biological product” and more specifically the term “protein” is meant to align with the statutory definition of “biological product” set forth in the BPCIA.16 The FDA determined that the term “protein” includes chemically synthesized proteins having a specific, defined sequence of amino acids, but does not include chemically synthesized polymers with random sequences.17 Notably, the FDA did not provide an interpretation of the term “analogous product” in the context of proteins.18
In December 2018, the FDA published “a notice of proposed rulemaking and a proposed rule to codify its interpretations of ‘protein’ and ‘chemically synthesized polypeptide.’”19 The same day, the FDA issued final draft guidance describing its interpretation of the “deemed to be a license” provision of the BPCIA, providing that conventional drugs approved as NDAs meeting the “biological product” definition, including certain “protein products,” can be reclassified as licensed biologic products known as “deemed BLAs.”20 The FDA also recommended sponsors of proposed “protein products” that may not be approved on or before March 23, 2020 “to facilitate alignment of product development plans” with the FDA’s interpretation of “biological product.”21
Didn’t Make The List
On March 23, 2020, the FDA published the final list of “deemed BLAs.” The list did not include the Teva product, Copaxone® (glatiramer acetate).22 The FDA determined: “[g]latiramer acetate is not a ‘protein’ because it does not have a specific, defined sequence,” a criterion “describ[ing] the manner in which specific amino acids are added to a polymer in a defined sequence;” and is not a product “analogous” to a protein.23
On March 24, 2020, a day after the FDA published the “deemed BLAs” list, Teva filed suit against the FDA in the D.C. Circuit seeking an order mandating the FDA to regulate Copaxone® as a “biological product” rather than as a “drug” product.24 Teva challenged the FDA’s determination that Copaxone® is “neither a protein nor a product analogous to a protein and therefore cannot be transitioned” from the Orange Book to the Purple Book.25 Notably, Teva owns two patents covering the process of manufacturing glatiramer acetate, which are not eligible for Orange Book listing.26 However, if Copaxone® was “deemed” a BLA, the same two patents could be subject to the “patent dance,” listed in the Purple Book, and litigated under the BPCIA framework.
The Court’s December 31, 2020 Memorandum Opinion held the FDA’s interpretation of the term “protein” is reasonable and owed deference.27 The Court also held that the FDA’s determination that: Copaxone® is not a protein is not “arbitrary or capricious;” and Copaxone® “is not ‘analogous’ to a protein was reasonable.”28 The Court found the FDA reasonably interpreted that molecules without a specific defined sequence are not proteins within the meaning of the BPCIA.29 Because the active ingredient of Copaxone®, glatiramer acetate, is a chemically-synthesized mixture of peptide copolymers30 and the sequences of the copolymers vary batch-to-batch during manufacturing, the Court agreed with the FDA’s determination that Copaxone® does not have a defined sequence, and therefore, does not qualify as a protein under the BPCIA.31
Interestingly, the Court distinguished Copaxone® from Vitrase® and Creon®, both of which are naturally-derived products and deemed “proteins” despite the fact that the active ingredients in both products vary batch-to-batch. The Court explains that Vitrase® and Creon® have molecular variations batch-to-batch, for example, one batch may contain a mixture of “HYAL1” and “HYAL2” molecules while another batch may contain a mixture of “HYAL1,” “HYAL2,” and “HYAL3” molecules; however, the sequence of “HYAL1” still has the same sequence across every batch.32 According to the Court, Copaxone® differs from these two products in that it has sequence variations batch-to-batch, i.e., the sequence of the single type of molecule, glatiramer acetate, is different batch-to-batch. The Court’s opinion demonstrates that naturally-derived biological products can readily be “deemed” biologics under the BPCIA and qualify for listing in the Purple Book whereas due to the undefined sequences, chemically-synthesized products could face significant challenges.
Purple is not the new orange. The Purple Book is distinct from the Orange Book, and is meant to cover biological products with defined sequence structures. To enjoy the benefits offered by the Purple Book, manufacturers should, during the initial planning stages, consider the feasibility of designing the biological product so that it can be made from a corresponding DNA and RNA sequence. Alternatively, manufacturers could consider improving the chemical synthesis process to achieve consistency and document evidence that the sequence of the biological product remains the same from batch-to-batch, if possible.
Footnotes
